The Involvement of Skeletal Muscle Stem Cells in the Pathology of Muscular Dystrophies 25–27 January 2019, Hoofddorp, the Netherlands
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Available online at www.sciencedirect.com Neuromuscular Disorders 29 (2019) 704–715 www.elsevier.com/locate/nmd Workshop report 240th ENMC workshop: The involvement of skeletal muscle stem cells in the pathology of muscular dystrophies 25–27 January 2019, Hoofddorp, The Netherlands a, b , ∗ c a, b d, ∗ Jennifer Morgan , Gillian Butler-Browne , Francesco Muntoni , Ketan Patel , on behalf of # the skeletal muscle stem cells involvement in pathology study group a University College London Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK b NIHR Great Ormond Street Hospital Biomedical Research Centre, 30 Guilford Street, London WC1N 1EH, UK c Center for Research in Myology, Association Institut de Myologie, Inserm, Sorbonne Université, 75013 Paris, France d School of Biological Sciences, University of Reading, Reading, RG6 6AS, UK Received 28 June 2019 1. Introduction be expressed either only within the muscle fibre to produce components of the dystrophin-associated protein complex, or Twenty-six participants representing patients, funding within cells lying outside the myofibre (e.g., by fibroblasts agencies and basic and clinical scientists involved in research (reviewed [1] ). Skeletal muscle needs to grow, maintain into skeletal muscle stem cells and muscular dystrophies from itself for a lifetime and also repair itself in response to France, Germany, Italy, India, UK, Australia, Spain, USA, injuries or increased load. In muscular dystrophies, skeletal The Netherlands and Switzerland met in Hoofddorp, The muscles undergo chronic intrinsic necrosis that gives rise to Netherlands on 25–27 January 2019. The meeting was held myogenesis and regeneration, in order to replace the necrotic under the auspices of the ENMC and ENMC main sponsors, portion of the myofibres. The satellite cell is the stem cell that with the additional support of Muscular Dystrophy UK. is involved in regeneration as well as skeletal muscle growth The central aim of this workshop was to determine and postnatal myogenesis and possibly hypertrophy. It sits in whether there could be some intrinsic problems with satellite a niche between the myofibre sarcolemma and basal lamina cell function (e.g., activation and myoblast proliferation, both of which regulate satellite cell quiescence, activation and differentiation and fusion) and consequently provide evidence self-renewal. for satellite cell involvement in pathology in major classes Expression of several genes responsible for muscular of muscular dystrophy and congenital myopathies. This is dystrophies and also for congenital myopathies were not most likely to manifest as impaired muscle formation during initially detected in satellite cells. These findings have major development in the congenital myopathies. However, some implications in that they support the idea that muscular problems in muscle formation may be due to extrinsic factors dystrophies do not arise from the malfunctioning of satellite in the microenvironment of the satellite cells/myoblasts, such cells and that correcting other compartments should be as altered composition of the extracellular matrix. sufficient to alleviate the disease. However with the advent Although they vary in many features including severity, of powerful detection methods it is becoming clear that muscle groups affected, age of onset and heart involvement, this conclusion is not generally sustainable. This is best muscular dystrophies are characterised by progressive skeletal exemplified by discoveries made in the field of Duchenne muscle weakness and wasting. They are generally caused Muscular Dystrophy (DMD). The involvement of the satellite by mutations in genes that have been historically thought to cell in DMD was thought to be a secondary response to the lack of dystrophin in the myofibre as well as an excessive proliferation of the satellite cells which in human have ∗ Corresponding authors. limited replicative potential due to telomere shortening. The E-mail addresses: [email protected] (J. Morgan), [email protected] (K. Patel). dystrophin-deficient myofibre undergoes necrosis and satellite # Listed at the end of this report. cells become activated, proliferate and then contribute to https://doi.org/10.1016/j.nmd.2019.07.003 0960-8966 J. Morgan, G. Butler-Browne and F. Muntoni et al. / Neuromuscular Disorders 29 (2019) 704–715 705 muscle regeneration and reconstitution of the satellite cell DMD, this talk first summarised the many persisting problems pool. In DMD, it was long held that the satellite cells with clinical applications of this muscle stem cell therapy fail in their myogenic capacity and ability to proliferate approach that need to be overcome. Key issues include after repeated episodes of muscle necrosis and regeneration. the source of ‘normal donor’ skeletal muscle stem cells, Muscle fibres become progressively replaced by fibrosis, an expansion in tissue culture, best route of delivery, massive adverse environment that also can impair myogenesis. initial death of injected cultured myogenic cells, and limited Recent findings show that dystrophin is expressed proliferation and migration in vivo , before fusion with the transiently in satellite cells and this is proposed to control host dystrophic muscle cells. These major problems need to their asymmetric divisions, so that satellite cells from the be realistically addressed when proposing stem cell therapies dystrophin-deficient mdx mouse model of DMD give rise for muscular dystrophies. Another therapeutic strategy for to a disproportionate number of stem-like satellite cells at delivering myogenic stem cells, is the exciting field of tissue the expense of differentiation-competent myoblast progenitors engineering that aims to build new muscle constructs to [2] . This observation raised the possibility of DMD being a replace muscles that are unable to regenerate due to some muscle stem cell disease. But this may be too simplistic, as impaired intrinsic capacity of muscle stem cells; while this there appears to be excellent myogenesis and new muscle holds great promise for many creative tissue culture studies formation by dystrophic satellite cells during growth of of muscle cells, there remain serious challenges for clinical mdx mice, and in tissue culture, that is maintained in the applications [8] . mdx mouse, even after persistent intrinsic myonecrosis of The critical issue of identifying whether there is any limb muscles over many months and after experimental intrinsic problem with satellite cell capacity for myogenesis muscle injury [3] , suggesting that dystrophin is not critical in DMD specifically, and other muscular dystrophies was then for satellite cell function under the experimental conditions addressed. This can be identified by some marked problems evaluated. with muscle formation during development (congenital The satellite cell dysfunction in mouse models of manifestation): not evident in mdx mice, nor conspicuous dystroglycanopathy [4] and collagen VI deficiency [5] may be for DMD baby boys. Then it is essential to determine due to defects in the environment (niche), rather than intrinsic histologically the extent of any ongoing intrinsic myofibre defects in the satellite cells themselves. But the extent to necrosis (thus the need for regeneration) in growing and adult which members of the DAPC are expressed in satellite cells muscles; however, care is needed when assessing biopsies and whether their expression within satellite cells is vital for since many morphological changes in muscles that can occur satellite cell function, is not clear. over time for other reasons (e.g., split myofibres, central Satellite cells also seem to have some direct effects on myonuclei) can sometimes be misinterpretated as resulting their environment and any disturbance in this may lead to from necrosis/regeneration [9] . If there is extensive intrinsic muscle pathology: it is proposed that satellite cells signal to necrosis, as evident in dystrophic rodent and dog models of fibroblasts to hold them in quiescence and loss of satellite DMD, then the capacity for sustained new muscle formation cells may increase muscle fibrosis. and regeneration needs to be determined: yet it is widely Mutations in genes that regulate satellite cell/myoblast reported that limb muscles of mdx mice have excellent activity are implicated in some congenital muscular sustained new muscle formation. However, one has to be dystrophies [6,7] . Here, altered behaviour of myoblasts prior cautious about concluding that the same properties exist to them fusing to form myofibres during embryogenesis and in the human without further evidence. The capacity for early growth results in impaired muscle formation evident at myogenesis (proliferation and fusion) of the satellite cells birth. can also be examined experimentally; in vitro studies show It is essential that we accurately assess the contribution of excellent myogenesis (equivalent to normal muscles) even for satellite cells to pathology of diverse muscular dystrophies, satellite cells cultured from old mdx mice aged 15 months [3] , since current therapies mostly aim at correcting abnormalities and in vivo studies using experimental muscle injury in mdx solely in the myofibre. This, if not addressed, will have major mice show very similar regenerative capacity for old mdx and implications on the long term efficacy of any treatment; if a normal muscles. defect in satellite cells is either the main, or a contributory, Thus overall, in animal models